Childhood Tuberculosis

檀卫平 中山二院 Tan-weiping

Definition Tuberculosis is caused by

Mycobacterium tuberculosis , isolated by Robert Koch in 1882 isolated by Robert Koch in 1882 , , M.bovis(seldom)M.bovis(seldom)

mainly involves the lungs, but may spread to other organs

consumption （肺痨）

Epidemiology 19th century, 25% deaths by TB 1940s, effective medicines Annually, 8 million become ill with

tuberculosis, 2 million people die China has the world's second largestChina has the world's second largest

tuberculosis epidemictuberculosis epidemic (after(after IndiaIndia),),1.3 million new cases every year

Work migrants "floating" peasants migrant population:100 million

incidencesincidences rates rates 113 per 100,000113 per 100,000 in in ChinaChina

Epidemiology The morbidity / mortality of The morbidity / mortality of

tuberculosis are high in developing tuberculosis are high in developing countriescountries(southeast asia,China,India,Africa,latin (southeast asia,China,India,Africa,latin america)america)

Age:60% Infant -<5yr Favored age:5-14yr Male:female-1:1(adults male

predominate)

Epidemiology TB adults exposure Immunocompromise malnutrition HIV/AIDS infection Poverty,immigration irregular treatment breeds :drug-

resistant tuberculosis

Risk factors Socioeconomic status Over-crowding Poor nutrition Inadequate health care HIV infection Drug abuse

EtiologyTubercle bacillus:Tubercle bacillus: aerobic,aerobic, grows slowlygrows slowly non-Motile,non-spore-non-Motile,non-spore-

forming, highlipid contentforming, highlipid content acid-fastacid-fast, , weak Gram(+)weak Gram(+) Sensitive to heat/sunlight Sensitive to heat/sunlight

tolerate in humid or dry or tolerate in humid or dry or cold. cold. withstand weak withstand weak disinfectantsdisinfectants and survive and survive in a in a dry statedry state for for weeksweeks..

Dr. Robert Koch discovered the tuberculosis bacilli

in 1882

He received the Nobel Prize in physiology or medicine in 1905 for this discovery

Tuberculosis is Tuberculosis is transmitted by transmitted by airborne dropletairborne droplet nuclei(containing nuclei(containing tubercle bacilli )tubercle bacilli )

prolonged, frequent, or intense contact

cough, sneeze, speak, or spit

Many droplet nuclei Many droplet nuclei are capable of floating are capable of floating in environment for in environment for several hoursseveral hours

Large particles may Large particles may be inhaled by personbe inhaled by person

breathing the same breathing the same air and impact on theair and impact on the

trachea or wall of trachea or wall of the upper airwaythe upper airway

The transmission is determined

The probability of contact with The probability of contact with active — not latent — TBactive — not latent — TB

intimacyintimacy and and durationduration of contact of contact effectiveness of ventilation numbernumbers and virulence of the M.

tuberculosis strain in infectious infectious dropletsdroplets

Pathogenesis

tubercle tubercle bacillus bacillus

Human immunity

Pathogenesis 90% infected with Mycobacterium

tuberculosis asymptomatic, latent TB infection 10% progress to TB disease

if untreated, the death rate for these active TB cases is more than 50%

Pathogenesis mycobacteria→pulmonary alveoli→replicate

within macrophages → picked up by dendritic cells →transport to local LN → spread through bloodstream to other tissues/organs → secondary TB lesions

primary site of infection :upper part of the lower lobe, or lower part of the upper lobe of lung

secondary TB lesions: apex of the upper lobes , peripheral lymph nodes, kidneys, brain, and bone

Human Immunity /hypersensitivity after TB infection Specific immunity after infected or Specific immunity after infected or

given BCG vaccinegiven BCG vaccine Cell-mediate immunity develops within Cell-mediate immunity develops within

4-8 weeks4-8 weeks after infected with bacillus after infected with bacillus Many immunologic cells:Many immunologic cells: Macrophages, Macrophages,

T/B lymphocytes, fibroblastsT/B lymphocytes, fibroblasts involvedinvolved

Two types of cells are essential in the formation of TB

Macrophages: directly phagocytize TB Macrophages: directly phagocytize TB and processing and presenting antigens and processing and presenting antigens to T lymphocyteto T lymphocyte

T lymphocytes(CD4+): induce protection T lymphocytes(CD4+): induce protection through the production of lymphokinesthrough the production of lymphokines

T lymphocytes(CD4+) Many lymphokines are involved in Many lymphokines are involved in

tuberculosis, the interplay of these tuberculosis, the interplay of these cytokines determine the hosts response cytokines determine the hosts response for examplefor example

IL-1 is related to feverIL-1 is related to fever IL-6 is related to hyperglobulinemiaIL-6 is related to hyperglobulinemia TNF is related to the killing of TNF is related to the killing of

mycobacteria formation of granulomasmycobacteria formation of granulomas other cytokines including IL-4,IL-5,IL-10 other cytokines including IL-4,IL-5,IL-10

can promote humoral immunitycan promote humoral immunity

Genetic factors (Genetic factors (HLA-BW35)HLA-BW35)play a key play a key role in innate non-immune resistance role in innate non-immune resistance to infection with M. Tuberculosis to infection with M. Tuberculosis

These genes may have a role in These genes may have a role in determining susceptibility to determining susceptibility to tuberculosistuberculosis

Basic pathologic changes

infiltrationinfiltration→→hyperplasia(hyperplasia(granuloma)granuloma),,

ulcerationulceration or or calcificationcalcification in different in different

stage stage

host defensehost defense< bacterias, bacterias, caseating caseating

ulceration(ulceration(caseous necrosiscaseous necrosis) →) →fibrosisfibrosis

host defense host defense >>bacteria, bacteria, granulomagranuloma

calcificationcalcification

A characteristic tubercle at low magnification (A) and in detail (B) central caseation surrounded by epithelioid and multinucleated giant cells(C) mycobacteria with acid-fast stains (D).

Progression of tuberculosis Absorption Fibrosis Calcification Deterioration: enlargement of

infected aeras and appear newer infiltrated regions or spreading.infiltrated regions or spreading.

Five common clinical patterns1. 1. Primary pulmonary tuberculosisPrimary pulmonary tuberculosis

(Primary Complex and(Primary Complex and Bronchial Lymphnode-Tuberculosis)Bronchial Lymphnode-Tuberculosis)2. 2. Milliary TuberculosisMilliary Tuberculosis (acute, subacute (acute, subacute

and chronic hematogenous pulmonary and chronic hematogenous pulmonary tuberculosis)tuberculosis)

3. 3. secondary pulmonary tuberculosissecondary pulmonary tuberculosis Infiltrative pulmonary tuberculosisInfiltrative pulmonary tuberculosis Chronic fibrocavenous pulmonary Chronic fibrocavenous pulmonary

tuberculosis tuberculosis 4.Tuberculous pleuritis4.Tuberculous pleuritis5.Extrapulmonary tuberculosis

Diagnosis History and Clinical Manifestations Tuberculin testingTuberculin testing Lab examination X-ray bronchoscopybronchoscopy Puncture of adenopathy

History /Clinical Manifestations

systemic signssystemic signs: fever, weight loss, fatigue, : fever, weight loss, fatigue, night sweats, wasting,coughing up blood,night sweats, wasting,coughing up blood,

Chest pain.Chest pain. TB Contaction ： adults in family History of BCG Vaccination Acute infectious disease recently :

measles,whooping cough Allergy to TB ： erythema

nodosum 、 herpetic conjunctivitis

Tuberculin skin test a skin test to determine past or present infection with the

tuberculosis bacterium; based on hypersensitivity of the skin to tuberculin

Method of test protein purified derivative PPD 0.1ml intradermal injection

Site: internal side of medium-distal 1/3 left forearm

6 - 10mm Result: 48-72hrs, transverse diameter

Result is read by measuring the diameter of induration 48-72hrs

Induration <5mm negative Induration 5-9mm(+) Induration 10-19mm(++) Induration 》 20mm (+++)

A positive tuberculin skin test indicates A positive tuberculin skin test indicates

tuberculous infection, with or without diseasetuberculous infection, with or without disease

Tuberculin testingTuberculin testing

A positive tuberculin A positive tuberculin test is of great use in test is of great use in children, with limited children, with limited diagnostic significance diagnostic significance in adultsin adults

Clinical Significance Positive Negative

Positive Reaction: indicates TB exposure

BCG Vaccination Children and adolescents(++) exposed

to TB Infant﹤3yrs (++) recent infection (+++) Active TB infectin (-) → (+) ， or Induration<10mm

→>10mm, ↑>6mm recent infection

Negative Reaction Never exposed to TB

Within 4-8wks of primary infectin

False negative:compromised immunity

Technique failure or PPD invalidated

PPD reaction of natural TB infection and BCG vaccination

Natural infection stronge Induration >10-15mm deep red 、 regular

margin 、 hard pigmentation Long duration > 7-10d Less change

BCG vaccination weak Induration 5-9mm light red 、

unregular margin 、 soft

Short duration:2-3d Become weak

gradually,disappear3-5y

Laboratory examinations

Sputum examination Sputum examination acid-fast stainingacid-fast staining

----LED microscopes

DNA-based diagnosis :PCR test TB :PCR test TB

antibody testingantibody testing

ESRESR

Blood RoutineBlood Routine

Isolation of M. tuberculosis automatic radiometric methods:

such as BACTEC—1-3wks

Chest radiographyChest radiography Chest X-ray: most important Chest X-ray: most important

method to detect TB method to detect TB Characteristics ,area, degree of Characteristics ,area, degree of

activity or progressactivity or progress Differentiation with other

disease Follow the effectivity of therapy

bronchoscopybronchoscopy

Endobrochial tuberculosis tuberculous tracheobronchial

lymphadenitis

Puncture of peripherial LN Tubercle caseous necrosiscaseous necrosis

Table 39-1   -- The Stages of Tuberculosis in Children

 

STAGE

Exposure Infection Disease

Skin test Negative PositivePositive (90%)

Physical examination

Normal NormalUsually abnormal

Chest radiograph

NormalUsually normal

Usually abnormal

TreatmentIf <5 years old

Always Always

Number of drugs

One One Three or four

The Stages of Tuberculosis in Children

Treatment Common therapy: Nutrition 、 Rest Ventilation Isolation

Chemotherapy

goal : Kill TB Limit TB from spreadingspreading principlesprinciples: earlier, appropriateearlier, appropriate Combination, Combination, Full course regularly andregularly and Staged..

Classification of antitubercular drug bactericidalbactericidal （ 1 ） complete bactericidalbactericidal ： INH 、 RFP （ 2 ） semi- bactericidalbactericidal ： SM ： alkaline, fast propagation, intracellular TB (Pyrazinamide) PZA ： Acidic 、 slow growth intracellular TB

medicines are classified as first-line medicines are classified as first-line and second-line agents and second-line agents

First-line essential antituberculous First-line essential antituberculous agents are the most effective and agents are the most effective and are necessary components ofare necessary components of

any short-course therapeutic regimenany short-course therapeutic regimen

First-line medicines includeFirst-line medicines include Isoniazid, rifampin,Isoniazid, rifampin, pyrazinamide,streptomycinepyrazinamide,streptomycine Second-line medicines includeSecond-line medicines include ethambutal, para-amino-salicylic acid,ethambutal, para-amino-salicylic acid, kanamycin, amikacin and ects.kanamycin, amikacin and ects.

Newer antituberculous drugsNewer antituberculous drugs rifapentine, rifabutin quinolonesrifapentine, rifabutin quinolones

Isoniazid (INH) first-line drug Isoniazid is a principal agent used Isoniazid is a principal agent used

to treat TBto treat TB It is universally accepted for initial It is universally accepted for initial

treatmenttreatment Now considered the best anti-TB Now considered the best anti-TB

drugdrug It should be included in all TB It should be included in all TB

treatment regimens unless the treatment regimens unless the organism is resistantorganism is resistant

Advantages InexpensiveInexpensive Readily synthesizedReadily synthesized Availabe worldwideAvailabe worldwide Highly selective for mycobacteriaHighly selective for mycobacteria Well tolerated(about only 5% of Well tolerated(about only 5% of

patients exhibiting adverse effectspatients exhibiting adverse effects))

Dosage

Tuberculosis organization have Tuberculosis organization have recommended recommended

5 mg/kg daily5 mg/kg daily for both groups for both groups Generally, Generally, 300mg daily300mg daily oral dose is oral dose is

adoptedadopted

Adverse effects

The two most important adverse effects of The two most important adverse effects of isoniazid therapy are isoniazid therapy are hepatotoxicityhepatotoxicity

peripheral neuropathyperipheral neuropathy We must measure liver enzymes before We must measure liver enzymes before

administrating and during treatment administrating and during treatment

periods(usually monthly measure)periods(usually monthly measure) If the liver enzymes level is higher than If the liver enzymes level is higher than

normal,the drug must be discontinuednormal,the drug must be discontinued

Rifampin (RFP) first-line drug

It is also considered the most important It is also considered the most important and potent antituberculous agentand potent antituberculous agent

Like isoniazid it is Like isoniazid it is bactericidalbactericidal and and highly effective highly effective

Unlike isoniazid, it is also effective Unlike isoniazid, it is also effective against most other mycobacteria as against most other mycobacteria as well as other organismswell as other organisms

Chemotherapy Regimens Standard regimen ： asymptomatic primary infection INH 、 RFP and/ （ or ） EMB 9-12 months

Two Stage Therapy Active primary TB 、 Disseminated

TB 、 TB meningitis Enforcement stage :3-4

bactericidalbactericidal ， 3-4m Consolidation stage :2 drug ， 12-18m

Short-term TherapyDOTS (Directly Observed Treatment Short-course)

2 or 3 drugs killing of organisms + 1 drug 2 or 3 drugs killing of organisms + 1 drug restraint of organismsrestraint of organisms

Mild/moderate with small infiltrates and Mild/moderate with small infiltrates and thin wall cavities :thin wall cavities :

INH+RFP+SM(EMB) (PZA)INH+RFP+SM(EMB) (PZA) 2 M or 2 M or INH+RFP 4 -7 MINH+RFP 4 -7 M extensive /severe, large areas of extensive /severe, large areas of

caseation or thick-walled cavities are caseation or thick-walled cavities are identified:identified:

INH+RFP+SM+EMB(PZA)INH+RFP+SM+EMB(PZA) 2 M or2 M or INH+RFPINH+RFP 4 -7 M 4 -7 M

Prevention Prevention of Tuberculosis :Vaccination BCG Vaccination can obtain immunity

acquired for tubercle bacillus. one of the most important tuberculosis prevention

Vaccination target: infants children and youngster of tuberculin negative (vaccination is of course of no use in tuberculin-positive persons)

Prevention Finding patients earlier Treatment and management of

patients Prevention with medicines The systemic organization of

prevention

Prophylatic chemotherapy Intimate contact with family members

suffering active TB <3y infant PPD test(++) without BCG

viccination PPD test (-) →(+) recently PPD test(++) accompanied by Tb toxic

symptoms PPD test(++) ， suffered

measles,whooping cough PPD test(++) and need long term

steroid therapy

Regimen:

INH ： 10mg/kg.d ， 6-9m

Tuberculous meningitis

Pathogenesis Spreading through bloodstreamSpreading through bloodstream Rupture of TB lesion→ bacteria

enter choroids plexuses → CSF Extension from nearby organ

infected with TB

Clinical Manifestation

The 1st Stage: 1-2wks change of character:irritability, Tb toxic symptom Headaches （ vomiting 、 drowsiness ）

The 2nd Stage 1-2wks Meningeal irritation stage Increased ICP:

Headaches,vomiting, drowsiness, seizure, nuchal rigidity, back pain, Kerning sign, Brudzinski sign.

Cranial Nerve palsy Encephalitis:disorentation,movem

ent disorders, speech impaiment, papilledema

The 3rd Stage Coma stage 1-3wks coma, hemiplegia, paraplegia,

convulsion consumption, abnormal metabolise of electrolyte

hypertenion, decerebrate posture brain hernia→ death

Diagnosis Medical history Clinical manifestation CSF examination Ｘ -ray check ＣＴ or ＭＲＩ scanning Tuberculin test

Differentiation diagnosis1. Meningococcal Meningitis2. Viral Meningitis3. cryptococcal meningitis 4. Cerebral tumor

Treatment General therapy Anti-tuberculous therapy Decreasing intracranial pressure corticosteroids Anti-symptomatic therapy Follow -up

Anti-tuberculous therapy

１、 The initial stage :　　３－４m　　ＩＮＨ、ＲＦＰ、ＰＺＡ、ＳＭ２、 The 2nd stage　　ＩＮＨ、ＲＦＰ　　１２m

Latent infection of tuberculosis A patient is infected with

Mycobacterium tuberculosis, but does not have active disease

Patients with latent tuberculosis are not infectious

The main risk is that approximately 10% of these patients will go on to develop active tuberculosis at a later stage of their life

The identification and treatment of people with latent TB is an important part of controlling this disease.

Miliary tuberculosis in an infant whose uncle also had tuberculosis. There is adenopathy in addition to the millet seed–like lesions

A posteroanterior (A) and lateral (B) chest radiograph of a child with hilar adenopathy caused by Mycobacterium tuberculosis.

Hilar and mediastinal adenopathy and a partial segmental lesion in a child with tuberculosis

Lobar pneumonia with bowing of the horizontal fissure in a child with tuberculosis. a secondary bacterial pneumonia may have been present

Tuberculous pleural effusion in a teenage girl. The pleural biopsy had caseating granulomas

A magnetic resonance image of tuberculoma in a child with culture-positive tuberculous meningitis. The child's presenting signs and symptoms included fever, altered mental status, and hemiparesis

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